X-tert



4-TERT.-HYDR( )CARBON-1,2-DIPHENYL-3,5- DIOXO-PYRAZOLIDINES AND PROCESSAlbrecht Heymons, Berlin-Nikolassee, Hans Volk, Berlin- Tempelhof, andHelmut Gansau, Berlin-Siemensstadt, Germany, assignors to FirmaRiedel-De Haen Aktiengesellschaft, Seelze, near Hannover, Germany, afirm of Germany No Drawing. Application December 14, 1954 Serial No.475,296

Claimspriority, application Germany January 8, 1954 9 Claims. Cl.260-610) The anti-pyretic and analgetic action-of 1,2-diaryl-3,5-

dioxo-pyrazolidines which are. substituted by a primary or secondaryalkyl group is known. Of these alkylatedderivatives,4-n-butyl-l,Z-diphenyl-Ia,S-dioxo-pyrazolidine,v more particularly, hasbeen able to achieve great significance and to. find a Wide-therapeuticemployment.-

It has now surprisingly been found that compounds with even morefavorable therapeutic properties thansthe" aforementioned 4-n-butylderivative are obtained if, in stead of. a primary or secondary alkylgroup, a tertiary alkyl group, and more particularly the tertiary butylgroup, is introduced into the 4-position of the1,2'-diphenyl-3,S-dioxo-pyrazolidines. It has further been found thatlike results are also obtained if the group in the 4-position is al-alkylcyclohexyl group. The-resultantl,2-diphenyl-3,5-dioxo-pyrazolidine derivatives, and particularly thatsubstituted bythe tertiary butyl group, are distinguished by anessentially lower toxicity and by an enhanced antiphlogistic actionwhile maintaining a comparable anti-pyretic and analgetic action, sothat the therapeutic breadth of the new compounds of the presentinvention is significantly greater and more favorable that that of theknown compounds of similar constitution. This effect is particularlyrealized, by the combination of the sodium salts of thenew pyrazolidinederivatives with 1-phenyl-2,3-dimethyl-4-dimethylamino pyrazolone, forwhich the new compounds of the present invention are excellent solvents.

The preferred 1,2-diphenyl-3,5-dioxo-4-tert. alkylpyrazolidinesaccording to the'present' invention correspond to the formula laHswherein each of R R and R stands for a lower (saturated) alkyl group orR and R together with the central tertiary carbon atom form a cyclohexylgroup and R is a lower alkyl group, and wherein the sum of the carbonatoms in R +R +R is at least 3 and at most 8. Thus, each of R R and Rmay be a methyl group; or each of R R and R may be an ethyl group; or Rand R may each be a methyl group while R is a propyl group; or one of RR and R may be methyl while the other two are ethyl; or R may be methyl,R ethyl and R propyl; or R and R may each be a propyl group while R is amethyl or ethyl group; or R and R together with the central tertiary Catom form a cylohexyl group and R is methyl, ethyl or propyl; etc.

The phenyl groups in the 1- and 2-p0sition may be substituted but suchsubstituents do not appear to add to the pharmacological activity of thecompounds.

The aforesaid 1,2-diphenyl-3,5-dioxo-4-tertl alkylpyrazolidines andl,2-diphenyl-3,S-dioxo-4-(1'-alkylcyclohexyl)-pyrazolidines formWell-defined salts with a wide variety of organic and inorganic bases,which bases and salts are therapeutically valuable because of theiranalgetic, antipyretic, antiphlogistic and sedative action;

Thus, administered orally, e. g. in tablet form, they; are useful in thetreatment of arthritic conditions, gouty conditions, and the like.

Preferred among the aforesaid salts are the sodium and magnesium saltsand those of ethylenediamine, triethanolamine and trimethylamine.

(lines of the above-indicated formula I by treating with anequimolecular' quantity of an appropriate base, e. g.-

with aqueous caustic soda, ethylenediamine, aqueous caustic potash,aqueous sodium carbonate solution, sodi-' um ethylate, etc.

The excellent therapeutic effect of the hitherto-unknown compounds ofthe present invention could not be foreseen since the literaturedescribes only the primary and secondary4-alkyl-1,2-diaryl-3,S-dioxopyrazolidines and of these only a very fewhave been found to be suitable for therapeutic purposes.

The new 1,2-diphenyl-3,5-dioxo-4-tert. alkylor -4-(-1'alkylcyclohexyl)-pyrazolidines are preferably prepared The synthesis inthis way of the aforesaid diphenyldioxo-pyrazoiidines which contain atertiary substituent in the 4-position is new in pyrazolidine chemistry.Such synthesis has to be regarded as unobvious and unexpected sincethere was a real reason to expect that the Grignard compounds wouldreact primarily with the pyrazolidinenitrogen and the two oxo groups,and that'- the balance of the concurrent-reactions would therefore be infavor of those reaction products which are not here desired.

1,2-diphenyl-3,5-dioxo-4-te1't. alkyl-pyrazolidines are obtained by theaction of alkylmagnesium halides on the" diphenyl-dioxo-alkylideneor-cyclohexylidene-pyrazolidines, and by the splitting (hydrolysis) of thethus-obtained intermediates.

The following examples set forth typical embodiments of the invention.In the said examples the parts and percentages, unless otherwiseindicated, are by Weight and the temperatures are in degrees centigrade.Parts by volume bear the same relationship to parts by weight as domilliliters to grams.

Example 1 To a conventionally prepared solution of 18.2 parts ofmethylmagnesium iodide in parts by volume of ether, there are slowlyadded dropwise 29.2 parts of 1,2-dipheny1-3,S-dioxo 4isopropylidene-pyrazolidine (prepared by boiling1,2-dipheny1-3,S-dioxo-pyrazolidine in acetone) in solution in -200parts by volume of ether. The mixture is then heated to boiling for /2hour. Upon cooling, water is added and the mixture is acidified with 10%hydrochloric acid. The resultant directly precipitated1,2-diphenyl-3,5-dioxo-4-tert. butyl-pyrazolidine, as well as thatisolated from the ether solution, is recrystallized from alcohol. It isin the form of fine colorless 2,830,995 Patented Apr. 15, 1958 The saltsare ad vantageously prepared from the corresponding pyrazoli=* It istherefore surprising that the desired needles and has a melting point of175". By reacting with an equivalent quantity of an alcoholicsodium-ethylate solution, evaporating off the greater portion of thealcohol, and precipitating with'ether, there is obtained thecorresponding sodium salt which is readily soluble'in water.

Example 2 A Grignard solution is preparedfrom 4.8 parts of magnesium and21.8 parts of ethyl bromide in 100 parts by volume of diethyl ether. Tothis solution, there is added, dropwise and while stirring, a solutionof 14.6 parts of 1,2-diphenyl-3,5-dioxo-4-isopropylidene-pyrazolidine in300 parts by volume of diethyl ether. Upon completion of the ensuingreaction, the obtained organometallic intermediate compound settles out.The ether is removed by decantation, after which ice-water is added tothe residue. After acidification with normal hydrochloric. acid, thecrude 1,2-diphenyl-3,5-dioxo-4-tert. amyl-pyrazolidine which is producedis isolated and dried. By recrystallization from toluene and then frommethanol, this product is obtained as fine colorless needles which .meltat.140.5 C. The yield amounts to about 60% of the theoretical yield.

2 In lieu of ethyl bromide, a corresponding quantity of ethyl iodide orof ethyl chloride may be used.

Example 3 Cl x-C 2 C 2: C CCHCO CHr-CH: C O NCeHs N-COH5 is in the formof fine colorless needles which melt at 181. The yield is about 60% ofthe theoretical.

Any other suitable hydrolyzing agent such, for example as dilutesulfuric acid, may be substituted for the hydrochloric acid, used by wayof illustration, in the foregoing examples.

Having thus disclosed the invention, what is claimed is:

1. A compound selected from the group consisting of compoundscorresponding to the formula wherein each of R R, and R stands for alower alkyl group and wherein R and R may together with the adjacentC-atom represent a cyclohexyl group, the sum of the carbon atoms in R +R+R being at least 3 and not more than 8, and the salts of such compoundswith bases.

2. 1,2-diphenyl-3,5-dioxo-4-tert. butyl-pyrazolidine.

3. The sodium salt of 1,2-diphenyl-3,5-dioXo-4-tert. butyl-pyrazolidine.I

4. 1,2-diphenyl-3,5-dioXo-4-tert. amyl-pyrazolidine.

5. 1,2-diphenyl-3,5-dioxo 4 (1'-methylcyclohexyl)- pyrazolidine.

6. A process for the preparation of a 1,2-diphenyl-3,5-dioxo-pyrazolidine containing a tertiary substituent in the 4-position,which comprises subjecting a member selected from the group consistingof a 1,2-diphenyl-3,5-dioxo- 4-alkylidene-pyrazolidine and a1,2-diphenyl-3,5-dioxo- 4-cyclohexylidene-pyrazolidine'to the action ofan alkylmagnesium halide and then subjecting the resultant product tothe action of hydrolyzing agent whereby the corresponding 4-tert.alkyl-substituted or 4-(1'-alkyl-cylohexyl) substituted 1,2diphenyl-3,S-dioxd-pyrazolidine results.

7. A process for the preparation of 1,2-diphenyl-3,5- dioxo-4-tert.butyl-pyrazolidine, which comprises subjecting1,2-diphenyl-3,5-dioxo-4-isopropylidene-pyrazolidine to the action ofmethylmagnesium iodide, and then subjecting the resultant productto theaction of dilute hydrochloric acid whereby hydrolytic splitting takesplace with formation of the 1,2-diphenyl-3,5-dioxo-4-tert.butyl-pyrazolidine.

8. A process for the preparation of 1,2-diphenyl-3,5- dioxo-4-tert.amyl-pyrazolidine, which comprises subjecting1,2-diphenyl-3,5-dioXo-4-isopropylidene-pyrazolidine to the action ofethylmagnesium bromide, and then subjecting the resultant product to theaction of dilute hydrochloric acid whereby hydrolytic splitting takesplace with formation of the 1,2-diphenyl-3,5-dioxo- 4-tert.amyl-pyrazolidine.

9. A process for the preparation of l,2-diphenyl-3,5-dioxo-4-(lf-methylcyclohexyl)-pyrazolidine, which comprises subjecting1,2-diphenyl-3,5-dioXo-4-cyclohexylidene-pyrazolidine to the action ofmethylmagnesium iodide, and then subjecting the resultant product to theaction of dilute hydrochloric acid whereby hydrolytic splitting takesplace with formation of the 1,2-diphenyl- 3-5-dioxo-4-(1-methylcyclohexyl) -pyrazolidine.

References-Cited in the file of this patent UNITED STATES PATENTS2,562,830 Stenzl July 31, 1951 FOREIGN PATENTS 646,597 Great BritainNov. 22, 1950 293,925 Switzerland Mar. 1, 1954

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDSCORRESPONDING TO THE FORMULA